Mutagenesis, Vol. 18, No. 3, 277-282,
May 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Variation in the extent of microsatellite instability in human cell lines with defects in different mismatch repair genes
1 Department of Pathology and Laboratory Medicine, 2 Department of Genetics and 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Mismatch repair deficiency results in the elevation of mutation rates in tumors, which is especially pronounced in simple repeat sequences (microsatellites). We have investigated the relationship between microsatellite mutagenesis and certain combinations of mutations in mismatch repair genes, using a frameshift reversion assay to determine the spontaneous mutation rates of a dinucleotide microsatellite in two cancer cell lines, HCT116, which has defects in hMLH1 and hMSH3, and HEC-1-A, which has defects in hPMS2 and hMSH6. We found a 10-fold difference in mutation rates between these two cell lines. In addition, a mutant hPMS2 allele, PMS134, which has been reported to have a dominant negative effect, was expressed in mismatch repair-proficient telomerase-immortalized hTERT-1604 fibroblasts and mutation rates were determined. Expression of PMS134 did not elevate mutation rates in hTERT-1604. Combined, these results suggest that mutations in different mismatch repair genes can lead to varying degrees of microsatellite instability. It is also likely that there is heterogeneity in the mutations that are acquired in the absence of mismatch repair, such that some mismatch repair-defective cancer cells also contain mutations in other genes coding for proteins involved in the maintenance of genetic stability.
4 To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, CB 7525 Brinkhous-Bullitt Building, Chapel Hill, NC 27599, USA. Tel: +1 919 966 6920; Fax: +1 919 843 4682; Email: rfarber{at}med.unc.edu
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